Coronary heart disease (CHD) is the most common cause of death in U.S. women. Observational studies consistently show that postmenopausal estrogen, with or without a progestin, reduces the risk of CHD, and there are several plausible mechanisms by which estrogen might protect the heart. Nevertheless, clinical trials to date have not demonstrated cardioprotection. If hormone levels play a role in determining CHD risk in postmenopausal women and HRT is to be used as a means of reducing that risk, the interactions of endogenous hormones, HRT, and CHD risk factors need further definition, in particular the effect of covariates. Individual characteristics such as basal hormone levels, body size, past hormone use, and lifestyle decisions may modify responses to HRT. This proposal focuses on four questions: 1) what factors determine circulating sex hormone levels in postmenopausal women, 2) what factors determine changes in sex hormone levels in response to hormone replacement therapy (HRT), 3) do endogenous sex hormone levels influence CHD risk factors in postmenopausal women, and 4) do changes in sex hormone levels with HRT predict the effect of HRT on CHD risk factors. These questions will be addressed by analyzing existing data from the Postmenopausal Estrogen / Progestin Interventions Trial (PEPI), a 3-year, multi-center, double-blind, placebo-controlled trial designed to compare the effect of estrogen alone and 3 estrogen/progestin HRT regimens vs placebo on selected CHD risk factors. There were 875 participants. Serum sex hormone levels, CHD risk factors, and potential covariates (including demographic characteristics, anthropometric measurements, reproductive history and lifestyle variables), determined at baseline and at 24 or 36 months of treatment, will be considered in the analyses. Results of this study will help define the differences between women with regard to endogenous sex hormone levels and responses to HRT, and the relation of sex hormones to CHD risk factors. These observations may aid in deciding whether individual women should use HRT and, if so, which regimen would provide the most benefit with the least risk.